Thirty years ago, the possibility for external closed-loop control of blood glucose (BG) levels in people with diabetes has been established with an instrument commercially known as the Biostator™, which used intravenous (i.v.) BG sampling and i.v. insulin and glucose delivery [1],[2],[3]. Recent studies of i.v. closed-loop control performed at the University of Virginia by Dr. Clarke (who has also been involved in the first Biostator™ studies) showed that i.v. control algorithms are capable of keeping BG levels within 10% from the preset targets during maintained euglycemia, descent into induced hypoglycemia, sustained hypoglycemia (at 50 mg/dl for 30 minutes), and controlled recovery [4]. However, i.v. closed-loop control is cumbersome and unsuited for outpatient use. Thus, increasing academic, industrial, and political effort has been focused on the development of minimally-invasive closed loop using subcutaneous (s.c.) systems using continuous glucose monitoring (CGM) and s.c. insulin delivery. Several s.c.-s.c. systems, generally using CGM coupled with insulin infusion pump and a control algorithm, have been tested [5],[6],[7],[8]. A recent United States Senate hearing emphasized the artificial pancreas initiative [9]. In September 2006 the Juvenile Diabetes Research Foundation (JDRF) initiated the Artificial Pancreas Project and funded six centers worldwide to carry closed-loop glucose control research [10]. These centers include the universities of Cambridge (England), Colorado, Santa Barbara, Stanford, Virginia, and Yale. So far, preliminary results have been reported from three closed-loop control studies conducted at Medtronic [8], Cambridge [6], and Yale using equipment provided by Medtronic MiniMed Inc.
The future development of the artificial pancreas will be greatly accelerated by employing mathematical modeling and computer simulation. Such in silico testing would provide direction for clinical studies, out-ruling ineffective control scenarios in a cost-effective manner. In the past two decades computer simulation and computer-aided design have made dramatic progress in all areas of design of complex engineering systems. A prime example is the Boeing 777 jetliner, which has been recognized as the first airplane to be 100% digitally designed and assembled in computer simulation environment. This virtual design has eliminated the need for many costly experiments and accelerated the development process. The final result has been impressive—the 777′s flight deck and passenger cabin received the Design Excellence Award of the Industrial Designers Society—the first time any airplane was recognized by the society [11]. In the area of diabetes, accurate prediction of clinical trials has been done by the Archimedes diabetes model [12], [13]; a company—Entelos, Inc.—specializes in predictive biosimulation and in particular is working on diabetes simulator. These existing diabetes simulators, however, are based on population models. As a result, their capabilities are limited to prediction of population averages that would be observed during clinical trials.
The ability to simulate glucose-insulin system in normal life condition can be very useful in diabetes research. Several simulation models have been proposed in literature which proved to be useful in tackling various aspects of pathophysiology of diabetes [32-42]. Recently a new meal simulation model was proposed in [43]. The novelty and strength of this model is that it is based on virtually model-independent measurements of the various glucose and insulin fluxes occurring during a meal [44, 45]. In fact, the system is very complex and only the availability of glucose and insulin fluxes, in addition to their plasma concentrations, has allowed us to minimize structural uncertainties in modeling the various processes. The model may comprise of 12 nonlinear differential equations, 18 algebraic equations and 35 parameters. A user-friendly simulation software of this model would be of great help especially for investigators without a specific expertise in modeling. An aspect of the present invention is to present the interactive software GIM (Glucose Insulin Model), implemented in MATLAB version 7.0.1 which allows to simulate both normal and pathological conditions, e.g. type 2 diabetes and open- and closed-loop insulin infusion in type 1 diabetes. These case studies are only presented to illustrate the potential of the software and do not aim to address pathophysiological questions or to assess quality of glucose control by different strategies
Therefore, for the purposes of artificial pancreas development, a different type of computer simulator is needed—a system that is capable of simulating the glucose-insulin dynamics of a particular person.